Evaluating New Treatment Options

Steven D. Nathan, MD

Another study performed a pooled analysis of CAPACITY and ASCEND data to assess all-cause mortality, treatment-emergent all-cause mortality, IPF-related mortality, and treatment-emergent IPF-related mortality at weeks 52, 72, and 120 in patients treated with either pirfenidone or placebo. The analysis demonstrated that the relative risk of death for all mortality outcomes studied was significantly lower in patients treated with pirfenidone versus those who received placebo in the pooled population (P = .0107). At the longest follow-up interval of 120 weeks, significant differences in the pooled analysis demonstrated a salutary effect for pirfenidone in terms of treatment-emergent all-cause mortality (P = .0420), IPF-related mortality (P = .0237), and treatment-emergent IPF-related mortality (P = .0132). A meta-analysis of the CAPACITY and ASCEND studies combined with those of 2 earlier Japanese trials of pirfenidone, Shionogi Phase 2 and Shionogi Phase 3, was also performed. This meta-analysis for all-cause mortality also demonstrated both a clinically relevant and significant risk reduction in the patients treated with pirfenidone versus those treated with placebo. This treatment benefit of pirfenidone therapy across multiple mortality outcome analyses provides additional evidence to support the use of pirfenidone in patients with IPF.10

Additional safety analyses of trial data have continued to demonstrate that long-term treatment with pirfenidone is safe and generally well tolerated. Lancaster et al assessed data from 1299 patients in the CAPACITY and ASCEND trials, along with data from 2 open-label RECAP studies (study 002 and 012), looking at safety outcomes during the period from administration of the first dose until 28 days after final study drug administration. A cumulative total exposure to pirfenidone of 3160 person-years was demonstrated across these trials. AEs found were generally mild to moderate in severity, with gastrointestinal (GI) events including nausea (37.6%), diarrhea (28.1%), dyspepsia (18.4%), and vomiting (15.9%). In addition, 25% of patients studied experienced a rash with pirfenidone treatment. Of note, alanine aminotransferase or aspartate aminotransferase elevations that were >3 times the upper limit of normal occurred in 3.1% of patients treated with pirfenidone; however, these elevations were generally transient and reversible with therapy dose modification or drug discontinuation, and were without significant clinical sequelae. Overall, this study followed patients prospectively for up to 9.9 years and found that long-term treatment with pirfenidone was safe and well tolerated in the treatment populations.11 Another analysis by Anderson et al, using comprehensive data from randomized clinical trials (RCTs), meta-analyses, safety studies, and postmarketing studies, was performed to assess the safety and efficacy of pirfenidone. This analysis confirmed that the drug was well tolerated, with a majority of AEs related to GI or skin complaints. The study did note that pirfenidone has been associated with neurologic AEs, including dizziness, fatigue, anxiety, drowsiness, and insomnia.12 This assessment noted that 1 meta-analysis of 6 clinical trials showed that pirfenidone had a significantly higher rate of neurologic AEs compared with placebo. However, it should be noted that among these neurologic AEs, only dizziness and fatigue actually occurred significantly more frequently in patients treated with pirfenidone.12,13

Patient Pearls for Therapy

In the analysis by Anderson et al, the authors note that pirfenidone is approved for treatment of IPF without mention of disease severity, leaving actual prescribing to the discretion of clinicians as to whether or not to use it in patients with more advanced disease. While clinical trial data in this area are sparse, observational data suggest benefit of pirfenidone in patients with this level of disease. The analysis notes that the key to success with pirfenidone is to maintain patients on therapy. Therefore, patient counseling and management of expectations is critical, along with managing any associated AEs. A mutual decision between patient/caregiver and treating clinician, with an emphasis on AE profiles, dosing, frequency, drug interactions, and patient preference, is crucial for successful therapy and patient management.12

Update of Most Recently Approved Therapeutic Options: Nintedanib

Phase 2 Trial

Nintedanib was assessed in 3 RCTs that were published in 2 separate reports. The first of these was a 12-month, phase 2 trial evaluating the efficacy and safety of 4 doses of nintedanib (then called BIBF 1120), 50 mg once or twice daily, 100 mg twice daily, and 150 mg twice daily versus placebo in 432 patients with idiopathic pulmonary fibrosis. The primary endpoint was the annual rate of decline of FVC, with secondary endpoints including acute exacerbations, quality of life as measured by the St. George’s Respiratory Questionnaire (SGRQ), and total lung capacity. Results demonstrated that FVC declined by 60 mL per year in the patients who received 150 mg of nintedanib twice daily compared with 190 mL per year in those who received placebo (P = .06 with the closed testing procedure for multiplicity correction; P = .01 with the hierarchical testing procedure), such that the percentage of patients with >10% FVC decline during the follow-up period was lower with the highest dose of nintedanib. This higher dosage also resulted in a lower incidence of acute exacerbations compared with placebo (P = .02), although patients treated with any dose of nintedanib had fewer IPF exacerbations. There was also a small decrease in the SGRQ score (P = .007, lower scores indicating better quality of life) versus an increase in SGRQ scores in the placebo cohort. AEs included GI symptoms, with more AEs and serious AEs in the treatment cohort, but these were not statistically significant. The conclusion was that the nintedanib 150-mg twice-daily dose was associated with a trend toward a reduction in the decline of lung function along with fewer acute disease exacerbations and preserved quality of life.6,14

The INPULSIS Trials

The INPULSIS trials (INPULSIS 1 and INPULSIS 2) were 2 replicate 52-week phase 3 RCTs to evaluate the efficacy and safety of the 150-mg twice-daily dose of nintedanib versus placebo. Similar to the earlier phase 2 trial, the primary endpoint was the annual rate of decline of FVC, with key secondary endpoints including the time to first acute exacerbation, and the change from baseline in the SGRQ, both assessed over the 52-week time period. Patients (N = 1066) were assigned to receive either nintedanib or placebo in a 3:2 ratio. Results from INPULSIS 1 showed that the annual rate of change in FVC was –114.7 mL in the patients who received nintedanib compared with a decline of –239.9 mL in patients in the placebo cohort (P <.001). In INPULSIS 2, the rate of FVC change was –113.6 mL with nintedanib versus –207.3 mL with placebo (P <.001). Fewer patients treated with nintedanib had a >10% decline in FVC over 52 weeks, although there was no significant benefit on mortality seen with nintedanib. In INPULSIS-1, there was no significant difference between the treatment and control cohorts in the time to first exacerbation (P = .67); however, in INPULSIS-2, there was a significant benefit seen with nintedanib versus placebo in time to first exacerbation (P = .005) (Figure 215). AEs were reported more significantly in the treatment cohort, with diarrhea reported by 61.5% of patients treated with nintedanib versus 18.6% of those treated with placebo. However, most patients continued to receive nintedanib for the entire trial period. The authors concluded that the data from INPULSIS demonstrated that nintedanib reduced the decline in FVC in patients with IPF, consistent with a slowing of IPF disease progression.6,15

Further Analyses

Patients who completed the INPULSIS trials could continue to receive nintedanib in an open-label extension trial, named INPULSIS-ON. Patients whose FVC was <50% of predicted were excluded from the INPULSIS 1 and 2 trials, but could participate in the extension trial. Patients in this trial received open-label nintedanib at either the 100-mg or the 150-mg twice-daily dosage, depending on previous dosing in INPULSIS, with dosing at the discretion of the investigator. An analysis of the first data in this patient population found that in patients with baseline FVC ≤50% predicted, the absolute mean change in FVC to week 48 of the extension trial was –62.3 mL versus a decline of –87.9 mL in those whose FVC was >50% predicted at baseline. No new safety signals were identified in INPULSIS-ON. Overall, the FVC decline in both baseline FVC groups in INPULSIS-ON was similar to that seen in patients treated with nintedanib in the original INPULSIS trials, suggesting a similar benefit on disease progression.16

In another study to assess whether patients with preserved lung volume would receive the same benefit from nintedanib as those with more impaired lung volume, the investigators performed a post hoc subgroup analysis of pooled data from the 2 INPULSIS trials using a baseline of ≤90% predicted vs >90% predicted FVC. This divided the patients studied into 2 groups, in which 274 patients had FVC >90% predicted and 787 patients had FVC ≤90% predicted. In patients treated with placebo in the original trials, the adjusted annual rate of decline in FVC was found to be consistent between both FVC cohorts; specifically, there was a decline of −224.6 mL/year for patients with FVC >90% predicted and −223.6 mL/year for those with FVC ≤90% predicted. Overall, the data analysis demonstrated no statistically significant difference between these subgroups in the effect of nintedanib on the annual rate of decline in FVC, change in SGRQ total score from baseline, or the time to first acute exacerbation. In patients whose baseline FVC was >90% predicted, the adjusted annual rate of decline in FVC with nintedanib was −91.5 mL/year (difference vs placebo: 133.1 mL/year) compared with −121.5 mL/year for those patients with baseline ≤90% predicted FVC mL/year (difference vs placebo: 102.1 mL/year). AEs associated with nintedanib treatment were similar in both subgroups. Overall, patients with IPF and FVC >90% predicted at baseline were found to have a similar rate of FVC decline and to receive the same benefits from nintedanib therapy as those with greater lung volume impairment, suggesting potential benefit and support to offering earlier treatment to patients with IPF.17